Shine a light: Under-ice light and its ecological implications in a changing Arctic Ocean.

The Arctic marine ecosystem is shaped by the seasonality of the solar cycle, spanning from 24-h light at the sea surface in summer to 24-h darkness in winter. The amount of light available for under-ice ecosystems is the result of different physical and biological processes that affect its path through atmosphere, snow, sea ice and water. In this article, we review the present state of knowledge of the abiotic (clouds, sea ice, snow, suspended matter) and biotic (sea ice algae and phytoplankton) controls on the underwater light field. We focus on how the available light affects the seasonal cycle of primary production (sympagic and pelagic) and discuss the sensitivity of ecosystems to changes in the light field based on model simulations. Lastly, we discuss predicted future changes in under-ice light as a consequence of climate change and their potential ecological implications, with the aim of providing a guide for future research.

Clot structure and fibrinolytic potential in patients with post thrombotic syndrome.

INTRODUCTION: Post-thrombotic syndrome (PTS) is a chronic sequel of deep vein thrombosis (DVT). The clot structure and fibrinolytic potential in PTS is currently unknown. OBJECTIVE: To assess the fibrinolytic potential and clot structure in patients with PTS. MATERIALS AND METHODS: Patients with a history of DVT were included in a case-control study: patients with PTS (cases n=30) and without PTS (controls n=30), and 30 apparently healthy individuals (HI) without venous thromboembolism (VTE) or venous insufficiency were enrolled. Fibrinolysis and clot structure were assessed by turbidimetric assays, permeation, and confocal microscopy. Fibrinogen was measured by Clauss and fibrinogen γ' by ELISA. RESULTS: We observed a significant trend of decreasing maximum turbidity from HI (median 0.52 [IQR 0.46-0.62]), to controls (0.49 [IQR 0.41-0.55]), to cases (0.46 [IQR 0.39-0.49]) p=0.020. Fibrinogen was lower in patients (cases and controls) (3.69g/L [IQR 3.31-4.26]) compared to HI (4.17 [IQR 3.69-4.65]) p=0.041. Patients with recurrent VTE had lower maximum turbidity and lower permeation than patients with one episode of VTE; (0.31 [IQR 0.25-0.39] versus 0.38 [IQR 0.34-0.44] p=0.008) and (6.0×10(-9)/cm(2) [IQR 5.1-7.9] versus 7.7×10(-9)/cm(2) [IQR 6.0-10.0] p=0.047) respectively, at equal fibrinogen levels. There were no differences in lysis time, confocal microscopy, or fibrinogen γ'. CONCLUSIONS: Lower maximum turbidity, indicating a tendency towards thinner fibres and denser clots, was found in patients with PTS as well as in patients with recurrent VTE. Fibrinogen levels did not explain these differences in clot structure. The abnormal clot structure may contribute to the increased thrombotic risk profile in patients with PTS.

Eliciting patients' preferences for elastic compression stocking therapy after deep vein thrombosis: potential for improving compliance.

UNLABELLED: ESSENTIALS: Elastic compression stocking (ECS) therapy is used to prevent post-thrombotic syndrome (PTS). We aimed to elicit patient preferences regarding ECS therapy after deep vein thrombosis. The most valued attributes were PTS risk reduction and the ability to put on the ECS independently. Heterogeneous results with respect to education level stress the importance of proper counselling. BACKGROUND: Elastic compression stocking (ECS) therapy is used for prevention of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT). Current evidence on its effectiveness is conflicting. Compliance, a major determinant of the effectiveness of ECS therapy, remained largely ignored in former studies. OBJECTIVES: To gain insight into preferences regarding ECS therapy in patients after DVT. PATIENTS/METHODS: A discrete choice experiment was conducted 3 months after DVT in patients enrolled in the IDEAL DVT study, a randomized controlled trial comparing 2 years of ECS therapy with individually tailored duration of ECS therapy for the prevention of PTS. Nine unlabeled, forced-choice sets of two hypothetical types of ECS were presented to each patient. Data were analyzed with multinomial logit models. RESULTS: The respondent sample consisted of 81% (300/369) of invited patients. The most important determinants of preference were PTS risk reduction and putting on the ECS. Patients were willing to increase the duration of therapy by 1 year if this increases the PTS risk reduction with 10%. Patients accepted an increase in the risk of PTS of 29% if they were able to put on the ECS themselves. Preferences were heterogeneous with respect to education level. CONCLUSIONS: Reduction of the risk of PTS and the ability to put on the ECS without help are the most important characteristics of ECS therapy. Physicians should pay considerable attention to patient education regarding PTS. In addition, patients should be supported in their ability to put on and take off the ECS independently. These rather simple interventions could improve compliance.

Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach.

BACKGROUND: Non-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. These advantages however are not included in the classic frequentist approach of sample size calculation for non-inferiority trials. In contrast, the decision theory approach of sample size calculation does include these factors. The objective of this study is to compare the conceptual and practical aspects of the frequentist approach and decision theory approach of sample size calculation for non-inferiority trials, thereby demonstrating that the decision theory approach is more appropriate for sample size calculation of non-inferiority trials. METHODS: The frequentist approach and decision theory approach of sample size calculation for non-inferiority trials are compared and applied to a case of a non-inferiority trial on individually tailored duration of elastic compression stocking therapy compared to two years elastic compression stocking therapy for the prevention of post thrombotic syndrome after deep vein thrombosis. RESULTS: The two approaches differ substantially in conceptual background, analytical approach, and input requirements. The sample size calculated according to the frequentist approach yielded 788 patients, using a power of 80% and a one-sided significance level of 5%. The decision theory approach indicated that the optimal sample size was 500 patients, with a net value of €92 million. CONCLUSIONS: This study demonstrates and explains the differences between the classic frequentist approach and the decision theory approach of sample size calculation for non-inferiority trials. We argue that the decision theory approach of sample size estimation is most suitable for sample size calculation of non-inferiority trials.

Biomarkers for post thrombotic syndrome: a case-control study.

INTRODUCTION: There is limited knowledge on the etiology of post thrombotic syndrome (PTS), although several mechanisms have been proposed. The objectives are to explore the role of different pathogenic mechanisms for PTS, through measurement of an elaborate panel of biomarkers in patients with and without PTS. MATERIALS AND METHODS: Patients with a history of deep vein thrombosis (DVT) with PTS (cases) and without PTS after minimal 2years follow-up (controls), were selected from the outpatient clinic of two Dutch hospitals. As a reference to the normal population healthy individuals (HI) without a history of venous thromboembolism were invited to participate. The population consisted of: 26 cases, 27 controls, and 26 HI. A panel of predefined biomarkers was measured in venous blood. RESULTS: D-dimer showed a decreasing trend from cases to controls to HI; p=0.010. Thrombin/antithrombin complex levels were significantly higher in cases than in controls; p=0.032, and HI; p=0.017. APC-ratio was significantly lower in cases compared to controls; p=0.032, and HI; p=0.011. A significant trend of increasing proTAFI from cases, to controls, and HI; p=0.002 was found. There were no differences in inflammatory markers (CRP, Interleukin-6, Interleukin-8). Thrombomodulin, tissue-plasminogen activator, and von Willebrand factor were higher in patients compared to HI. There was a significant trend of decreasing sVCAM, from cases, to controls, and HI; p=0.029. CONCLUSIONS: Patients with PTS displayed increased coagulation activity, an altered pattern of fibrinolytic marker expression, and increased endothelial activation. We found no evidence of systemic inflammation in patients with PTS at 63months since the last DVT.

Markers of coagulation, fibrinolysis and inflammation in relation to post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) occurs in 20-50% of patients after a deep venous thrombosis (DVT). It is difficult to accurately predict which patients will develop PTS. Biomarkers could be a valuable tool for PTS risk assessment. OBJECTIVES: To investigate whether increased levels of factor (F)VIII, C-reactive protein (CRP) or D-dimer, over time, are associated with the development of PTS in patients after an acute DVT. METHODS: PTS status was assessed using the Villalta scale. Blood sampling was performed at three points during follow-up. RESULTS: A cohort of 228 consecutive patients was included after an acute DVT. At T1 (12 months after index DVT), both levels of D-dimer (median 725 ng mL(-1) [interquartile range, IQR 400-1400[ vs. 378 ng mL(-1) [251-652] P=0.004) and CRP (median 3.9 mg L(-1) [IQR 1.6-8.5] vs. 2.4 mg L(-1) [1.0-4.3] P=0.018) were increased in patients with PTS, compared with patients without PTS. Factor (F)VIII was not associated with PTS. In the multivariate logistic regression analysis, varicosities (odds ratio [OR] 13.4 95% confidence interval [CI] 3.0-59.1 P=0.001), a previous ipsilateral DVT (OR 6.3 95% CI 1.5-26.9 P=0.012) and CRP>5 mg L(-1) on T1 (OR 8.0 95% CI 2.4-26.4 P=0.001) were significantly associated with PTS. CONCLUSIONS: Besides previous ipsilateral DVT and varicosities, CRP>5 mg L(-1) at T1 was strongly and independently associated with PTS. Persistent inflammation rather than hypercoagulability might be the most important etiological factor in PTS, and may be a target for future therapy. The development of a risk score for PTS, including both clinical risk factors and biomarker levels, such as CRP, might be desirable.

Evaluation of Qualidem: a dementia-specific quality of life instrument for persons with dementia in residential settings; scalability and reliability of subscales in four Dutch field surveys.

OBJECTIVE: To evaluate the scalability and reliability of Qualidem, a quality of life observation instrument rated by professional caregivers of persons with mild to very severe dementia living in residential settings. METHOD: Data from four field surveys in the Netherlands were used. The instrument consists of nine subscales for mild to severe dementia; of which six can be applied in very severe dementia. The Mokken scaling model was used to compute scalability and reliability coefficients for each subscale and dementia group. RESULTS: Seven hundred fifty nine persons with mild to severe dementia and 214 persons with very severe dementia residing in 36 nursing homes and 4 homes for the elderly were included. In general, the subscales for the mild to severely demented group were scalable and (moderate) sufficiently reliable; the results confirmed the results of previous research to develop Qualidem. For the very severe demented group, four out of six subscales were scalable (Care relationship, H = 0.56; Positive affect, H = 0.55; Restless tense behavior, H = 0.42; and Social isolation, H = 0.34); they were also sufficiently reliable to measure quality of life (0.57 ≤ ρ ≤ 0.82). From the other two measured subscales, Social relations was considered not scalable (H = 0.26) and Negative affect was scalable (H = 0.36), but insufficiently reliable (ρ = 0.40). CONCLUSION: Qualidem is an easy to administer and overall moderately sufficient reliable rating scale that provides a quality of life profile of persons with mild to even very severe dementia living in residential settings.

Prevalence of testicular adrenal rest tissue in neonates.

BACKGROUND: Infertility is a serious complication among male congenital adrenal hyperplasia (CAH) patients which is often caused by testicular adrenal rest tumors (TART). TART are already present in childhood and early infancy in CAH patients. The incidence of TART in neonates without CAH has not yet been described in detail before. OBJECTIVE: To study the prevalence of testicular adrenal rests in non-CAH neonates. DESIGN: Descriptive study. SETTING: Radboud University Nijmegen Medical Centre, The Netherlands. PATIENTS AND METHODS: 115 testis samples of 89 male infants without CAH who died within the neonatal period were histologically examined. MAIN OUTCOME MEASURES: Prevalence of adrenal rest tissue in the neonatal testes. RESULTS: Adrenal rests were found in 4 samples (3.5%). These adrenal nodules were all located within the epididymis; only in 1 sample a nodule was found close to the rete testis but still within the caput of the epididymis. No nodules were found within the testes. Of the 4 children with adrenal rests, 3 had urological malformations. CONCLUSION: The incidence of testicular adrenal rests in non-CAH neonates is low. Further studies are necessary to study the incidence of TART in CAH infants and detect typical risk factors in this patient group.

Colonoscopy-controlled intra-individual comparisons to screen relevant neoplasia: faecal immunochemical test vs. guaiac-based faecal occult blood test.

BACKGROUND: Guaiac-based faecal occult blood tests (g-FOBTs) are most commonly used in colorectal cancer (CRC) screening programmes. Faecal immunochemical tests (FITs) are thought to be superior. AIM: To compare performance of a g-FOBT and a quantitative FIT for detection of CRCs and advanced adenomas in a colonoscopy-controlled population. METHODS: We assessed sensitivity and specificity of both FIT (OC-sensor) and g-FOBT (Hemoccult-II) prior to patients' scheduled colonoscopies. RESULTS: Of the 62 invasive cancers detected in 1821 individuals, g-FOBT was positive in 46 and FIT in 54 (74.2% vs. 87.1%, P = 0.02). Among 194 patients with advanced adenomas, g-FOBT was positive in 35 and FIT in 69 (18.0% vs. 35.6%, P < 0.001). Sensitivity for screen relevant tumours (197 advanced adenomas and 28 stage I or II cancers) was 23.0% for g-FOBT and 40.5% for FIT (P < 0.001). Specificity of g-FOBT compared to FIT for the detection of cancer was 95.7% vs. 91.0%, P < 0.001) and for advanced adenomas (97.4% vs. 94.2%, P < 0.001). CONCLUSIONS: Faecal immunochemical test is more sensitive for CRC and advanced adenomas. Sensitivity of FIT for screen relevant tumours, early-stage cancers and advanced adenomas, is significantly higher. Specificity of g-FOBT is higher compared with FIT.

Is the Alifax Test-1TH useful to determine the Disease Activity Score (DAS28) in rheumatoid arthritis patients?

Treatment of rheumatoid arthritis (RA) is monitored with the disease activity score (DAS28), for which the erythrocyte sedimentation rate (ESR) is needed. Apart from the original gold standard method, other methods like the Alifax Test-1TH apparatus are widely used in laboratory worldwide. We compared ESR values obtained by the Alifax Test-1Th apparatus and the gold standard method for 218 RA patients. We found a good correlation (r=0.87) between the Alifax Test-1TH results and the gold standard method. A good correlation (r=0.96) was also found for the DAS28 results obtained with both methods. The number of patients that were misclassified when the Alifax Test-1TH is used is reasonable for both the ESR (14.7%) and the DAS28 (10.6%). These results suggest that it may be useful to determine the ESR by the Alifax Test-1TH, with a DAS28 misclassification in less than 11% of the patients.

Using the Maslach Burnout Inventory among dentists: burnout measurement and trends.

OBJECTIVES: To extend our knowledge about the applicability of the Maslach Burnout Inventory (MBI) among dentists and to investigate trends in burnout risk among dental professionals. METHODS: The structure of the MBI is examined among two independent, representative samples of dentists (n = 493 and 497, respectively). Moreover, results are compared to those of other independently-practicing health professionals (i.e., general practitioners and physiotherapists). In addition, the percentage of dentists that are at risk for burnout are compared in samples from 1997, 2000, and 2001. RESULTS: Correlations between the Emotional Exhaustion and Depersonalization subscales among dentists were higher than those found elsewhere. Additionally, a considerable increase in burnout risk was found since 1997. CONCLUSIONS: It was confirmed that the MBI can be considered a suitable instrument for use among dentists. It is argued that certain specific aspects of entrepreneur-like occupations are reflected in deviating responses to the MBI. Given the clear increase in burnout risk found, this topic should remain under investigation among dentists.

The immune response during the luteal phase of the ovarian cycle: increasing sensitivity of human monocytes to endotoxin.

OBJECTIVE: To test the hypothesis that during the luteal phase of the human ovarian cycle, as compared with the follicular phase, the percentage of cytokines producing peripheral monocytes after in vitro stimulation with endotoxin is increased. DESIGN: Prospective study. SETTING: Academic research institution. PATIENT(S): Women with regular menstrual cycles. INTERVENTION(S): Blood samples were collected between days 6 and 9 of the menstrual cycle (follicular phase) and between days 6 and 9 of the menstrual cycle following the LH surge (luteal phase). MAIN OUTCOME MEASURE(S): Percentages of tumor necrosis factor (TNF)-alpha-, interleukin (IL)-1 beta-, and IL-12-producing monocytes as well as total white blood cell (WBC) count, differential WBC counts, and plasma 17 beta-estradiol and progesterone concentrations. RESULT(S): Mean plasma 17 beta-estradiol and progesterone concentrations, percentage of TNF-alpha- and IL-1 beta-producing monocytes, WBC counts, and granulocyte cell count were significantly increased in the luteal phase as compared with the follicular phase of the ovarian cycle. The percentage of IL-12-producing monocytes, monocyte count and lymphocyte count did not vary between the 2 phases of the ovarian cycle. CONCLUSION(S): Together with an increase in progesterone and 17 beta-estradiol during the luteal phase, there is an increase in percentage TNF-alpha- and IL-1 beta-producing peripheral monocytes after in vitro stimulation with endotoxin as compared with the follicular phase of the ovarian cycle. Whether this increased sensitivity of monocytes for proinflammatory stimuli during the luteal phase is due to increased plasma levels of progesterone or 17 beta-estradiol needs further investigation.

Cytokine production by natural killer lymphocytes in follicular and luteal phase of the ovarian cycle in humans.

PROBLEM: The aim of this study was to test the hypothesis that, during luteal phase of the ovarian cycle, as compared with follicular phase, the cytokine productive capacity of peripheral natural killer (NK)-lymphocytes in humans is shifted towards a "Th2-type"-like response. METHOD OF STUDY: Intracellular Th1 and Th2 cytokine production by in vitro activated peripheral NK-lymphocytes in a whole blood preparation of the follicular and the luteal phase of the ovarian cycle was measured by flow cytometry. RESULTS: There was no difference in interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and IL-10 cytokine production in activated NK-lymphocytes when comparing luteal phase with follicular phase of the ovarian cycle. However, there was a significant increase in peripheral NK-lymphocyte number in luteal phase compared with follicular phase. CONCLUSION: The cytokine productive capacity of peripheral NK-lymphocytes is not shifted towards a "Th2-type"-like response in the luteal phase as compared with the follicular phase of the ovarian cycle in humans.

The immune response during the luteal phase of the ovarian cycle: a Th2-type response?

OBJECTIVE: To test the hypothesis that during the luteal phase of the ovarian cycle, as compared with the follicular phase, the peripheral immune response is shifted toward a type-2 response. DESIGN: Prospective study. SETTING: Academic research setting. PATIENT(S): Women with regular menstrual cycles. INTERVENTION(S): Blood samples were collected between days 6 and 9 of the menstrual cycle and 6-9 days after the LH surge. MAIN OUTCOME MEASURE(S): Intracellular cytokine production of interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and IL-10 after in vitro stimulation of lymphocytes as well as total white blood cell (WBC) count, differential WBC count, and plasma 17 beta-E(2) and P concentrations. RESULT(S): Mean plasma 17 beta-E(2) and P concentrations, WBC count, and mean granulocyte, monocyte, and lymphocyte counts were significantly increased in the luteal phase as compared with the follicular phase of the ovarian cycle. Production of type-1 cytokines (IFN-gamma and IL-2) and production of the type-2 cytokine IL-10 did not vary between the phases of the ovarian cycle. Production of the type-2 cytokine IL-4, however, was significantly increased in the luteal phase as compared with the follicular phase of the ovarian cycle. CONCLUSION(S): During the luteal phase of the ovarian cycle, the immune response is shifted toward a Th2-type response, as reflected by increased IL-4 production in this phase of the cycle. These results may suggest that increased levels of P and 17 beta-E(2) in the luteal phase of the ovarian cycle play a role in the deviation of the immune response toward a type-2 response.

Plasma creatinine assessment in creatine deficiency: A diagnostic pitfall.

Guanidinoacetate methyltransferase (GAMT) deficiency (creatine deficiency syndrome) is a recently discovered inborn error of creatine biosynthesis. Affected patients have elevated concentrations of guanidino-acetate, the metabolic precursor of creatine, in urine, plasma and cerebrospinal fluid. In addition, urinary creatinine excretion and plasma creatinine concentration are decreased. For biochemical evaluation of patients suspected to suffer from GAMT deficiency, correct quantification of creatinine in plasma is important. Here we report our experience with different quantification techniques. We found that creatinine in plasma from two GAMT-deficient patients appeared normal when measured by the Jaffé method but was decreased when measured enzymatically or by HPLC. The apparently normal levels of creatinine as measured by the Jaffé method were not caused by guanidinoacetate. In urine, the Jaffé method and the enzymatic method gave similar results, indicating that in urine no false elevations of creatinine can be expected. As the Jaffé method is still widely used for routine plasma creatinine measurements, it is important to realize it cannot be used to exclude GAMT deficiency.

Villoglandular papillary adenocarcinoma of the cervix. Beware of a wolf in sheep's clothing.

Villoglandular papillary adenocarcinoma of the cervix is a well differentiated form of cervical adenocarcinoma with a favourable prognosis and a conservative procedure is suggested. We present three cases of villoglandular papillary adenocarcinoma of the cervix. Histological examination of a biopsy of each cervix showed well differentiated villoglandular papillary adenocarcinoma, stage Ib according to FIGO classification. In all cases the disease was limited to the cervix. Nevertheless, histopathological examination of the surgical specimen revealed an infiltrating component with squamous differentiation in one case, while in a second case histopathological examination revealed a moderately differentiated papillary adenocarcinoma with a superficially infiltrating growth-pattern besides the villoglandular papillary adenocarcinoma. Before conservative therapy is considered, careful evaluation of the presence of poor prognostic features must be made. One should consider whether conservative therapy is sufficient because of the predominance of concomitance of other carcinoma besides the villoglandular papillary adenocarcinoma.

Maternal and fetal plasma concentrations of endothelin, lipidhydroperoxides, glutathione peroxidase and fibronectin in relation to abnormal umbilical artery velocimetry.

OBJECTIVE: To study plasma concentrations of endothelin (ET), lipidhydroperoxides (LOOH), glutathione peroxidase (GSHpx) and fibronectin in relation to abnormal umbilical artery velocimetry. STUDY DESIGN: Plasma concentrations of ET, LOOH, GSHpx and fibronectin were measured in fetal and maternal venous blood in: (i) a control group (n=10); (ii) in pregnancies complicated by intrauterine growth retardation (IUGR) (n=6) or preeclampsia (n=5) with positive end diastolic flow; and in (iii) pregnancies complicated by absent or reversed end diastolic (ARED) flow in the umbilical artery (n=18). All children were delivered by primary caesarean section. RESULTS: The significantly highest maternal and fetal ET concentrations were found in plasma collected in pregnancies complicated by ARED flow in the umbilical artery. Maternal fibronectin levels were significantly raised in the ARED flow group. Maternal plasma ET levels were lowest in pregnancies complicated by IUGR. The maternal and fetal plasma concentrations of LOOH and GSHpx did not differ significantly between the groups. CONCLUSION: Abnormal Doppler velocimetry, especially ARED flow is associated with elevated maternal and fetal plasma levels of ET. The exact mechanism causing the placental vasoconstriction is unknown yet, but oxidative stress seems not to be involved.

Glutathione S-transferase activity and subunit composition in transitional cell cancer and mucosa of the human bladder.

OBJECTIVES: Clinical data indicate that drug resistance to chemotherapy may occur in all stages of transitional cell cancer (TCC). Glutathione S-transferases (GSTs) are a family of detoxification enzymes composed of four different classes, denoted alpha (GSTA), mu (GSTM), pi (GSTP), and theta (GSTT), each containing one or more homo- or heterodimeric isoforms (GSTA1-1, GSTA1-2, and so forth), GSTs play a prominent role in drug detoxification and have been associated with resistance of tumor cells to anticancer agents. GST activity and isoenzyme levels were studied in TCC and normal bladder mucosa. METHODS: Enzyme activity was studied in samples of TCC (n = 37), adjacent normal bladder mucosa (n = 37), and in bladder mucosa of control patients without TCC (n = 46). GST isoenzyme composition was studied in mucosa and TCC of 14 patients and 11 controls. RESULTS: The mucosa of patients with TCC showed GST activity (191 +/- 21 nmol/min/mg cytosolic protein), similar to the mucosa of controls (176 +/- 15 nmol/min/mg). GST activity was significantly increased in TCC (666 +/- 157 nmol/min/mg) in comparison with adjacent mucosa (P < 0.003). In mucosa samples, the levels of GSTA (A1-1, A1-2, and A2-2) were below the detection limit in 92% of the samples. GSTM (GSTM1-1) was found in 9 controls and in 7 patients with TCC but not in the other 7 patients, whereas GSTP (GSTP1-1) could be detected in all samples. The levels of GSTM1-1 and GSTP1-1 were similar in mucosa of patients and controls. The mean relative increase of GSTP1-1 levels in TCC was 4.6-fold (P < 0.002). In the 7 patients with GSTM1-1-detectable expression in adjacent normal mucosa, mean GSTM1-1 levels in TCC were increased 2.8-fold compared with mean levels in normal adjacent mucosa (P < 0.02). GSTA was measured in five samples of TCC at relatively low levels. CONCLUSIONS: Overexpression of GSTP1-1 and GSTM1-1 may suggest that in the process of TCC carcinogenesis, a selection pressure occurs, resulting in a tumor with enhanced detoxification properties, including that of therapeutic drugs.

Continuously combined hormone replacement therapy and bone turnover: the influence of dydrogesterone dose, smoking and initial degree of bone turnover.

In this study we examined whether the effect of continuously combined hormone replacement therapy (HRT) on bone metabolism is influenced by dydrogesterone dose, smoking and initial degree of bone turnover. In a double-blind randomized study, 123 healthy postmenopausal women (mean age 51.7 years; range 30-61 years) received 17 beta-estradiol, 2 mg orally per day, continuously combined with either 2.5, 5, 10 or 15 mg of dydrogesterone daily. At baseline and at 3 and 6 months of therapy, bone formation was assessed by determining total alkaline phosphatase (TAP), bone-derived alkaline phosphatase (BAP), and the carboxy-terminal propeptide of collagen type I (PICP) in serum; bone resorption was assessed by the calcium/creatinine (Ca/Creat) and hydroxyproline/creatinine (Hp/Creat) ratio in 2-h fasting urine, and the serum carboxy-terminal pyridinolyne cross-linked telopeptide of collagen type I (ICTP). Dydrogesterone dose did not influence the effect of HRT on any of the bone markers. Combining the data of the four treatment groups, the decrease in each marker, compared to baseline values, was significant. However, in non-smokers, compared to smokers, after 6 months of therapy the decline in BAP and TAP was significantly more pronounced and the plasma estradiol level was significantly higher. For each bonemarker at baseline, women in the highest quartile, compared to women in the lowest quartile, showed a significantly stronger decrease in this marker in response to HRT. We conclude that dydrogesterone dose does not modify the effectiveness of replacement therapy. However, smoking and a low bone turnover at baseline may diminish its beneficial effect on bone.

Immunoadsorption assay for bone alkaline phosphatase compared with wheat germ agglutinin precipitation assay in serum from (pre)pubertal girls.

The performance characteristics of two bone alkaline phosphatase (ALP; EC 3.1.3.1) assays, a wheat germ agglutinin (WGA) precipitation assay and a new immunoadsorption assay (IAA), were compared. The within- and between-run imprecision of the IAA (3.6-4.2% and 3.6-7.7%) was comparable with that of the WGA assay. The mean cross-reactivity with liver ALP appeared to be 4% in the WGA assay and 11% in the IAA. The reference ranges in a group of 155 healthy Caucasian (pre)pubertal schoolgirls were: 149-401 U/L (total ALP, 30 degrees C), 105-349 U/L (bone ALP, 30 degrees C, WGA assay), and 58-205 U/L (bone ALP, 25 degrees C, IAA). Comparison of the WGA assay (x) with the IAA (y) demonstrated a correlation coefficient of 0.95 [Deming regression equation: y = (0.56 +/- 0.01)x + (2.0 +/- 1.5); Sy[symbol: see text]x = 5.3 U/L]. Correlation studies of the WGA assay and the IAA results with total ALP demonstrated r = 0.98 and 0.96, respectively.